How physiological responses to alterations in dietary intake affect the process of aging and longevity is a fundamental question to understand the systemic regulation of the complex connection between metabolism and aging. Diet restriction (DR), the single, most reliable regimen known to retard aging and extend lifespan in a variety of organisms, has provided a unique model to address this important question. This research proposal aims to understand molecular mechanisms underlying physiological adaptive responses to DR, particularly the central adaptive response, in mammals. We have been interested in the evolutionarily conserved SIR2 (silent information regulator 2) family of NAD-dependent deacetylases/ADP-ribosyltransferases, also called "sirtuins," as a critical regulator that coordinates physiological responses to DR. Our new study has recently demonstrated a novel function of the mammalian SIR2 ortholog SIRT1 in the hypothalamus, particularly in the dorsomedial and lateral hypothalamic nuclei (DMH and LH, respectively), as a key mediator that controls the orexin type 2 receptor (OX2R)-mediated signaling in response to peripheral signals including ghrelin, an orexigenic hormone secreted from stomach, induced by DR. Therefore, in this proposal, we hypothesize that SIRT1 controls central adaptive responses to DR, including the augmentation of physical activity and the maintenance of body temperature, through the up-regulation of the Ox2r expression and the neural activation in the DHM and LH. To address this hypothesis, we will examine 1) how SIRT1 up-regulates the transcription of the Ox2r gene through a newly identified target homeodomain transcription factor in response to DR, 2) whether stereotactic injection of lentiviruses expressing shRNA against Sirt1 or the SIRT1 target transcription factor into the DMH and/or LH abrogates the central adaptive response to DR, 3) how SIRT1 activity is augmented by DR in the DMH and LH, and 4) whether SIRT1-mediated central adaptive response is also important for the control of longevity in mice. Because very little has been known about the central adaptive mechanism for DR, the proposed study will provide critical insights into the physiological mechanism that orchestrates responses to DR and may assure longevity in mammals. PUBLIC HEALTH RELEVANCE: The proposed study will ultimately enhance our understanding of the regulation of metabolism and aging in mammals and provide critical insights into possible anti-aging interventions in humans for the following reasons: First, this study will elucidate the importance of a novel central regulatory circuit involving SIRT1 and orexin signaling in the hypothalamus. Second, the proposed study will shed a new light on the importance of a specific subset of neurons, namely, OX2R-positive neurons in the DMH and LH, in the regulation of central adaptive responses to DR. Lastly, this study will provide important support for the concept of the NAD World that we have recently proposed and also open a new possibility to develop nutriceutical interventions for age- associated neurological complications, including complications of ingestive behavior in the elderly, called "the anorexia of aging."